Additionally, our present study is limited to the detection of EnV strains present in Hawaii, which may not be a complete representation of the EnV composition present elsewhere

erved in the JWAD2/D2 mice might be also partially contributed by the similar mechanisms of premature ageing like phenotype, however, the exact molecular evidences need to be further provided. To exclude the contribution of non cell autonomous effects in skin tumor phenotypes observed in the full knockout mice, future studies XAV-939 web should include the conditional deletion of this gene from the skin. In summary, we demonstrate for the first time that JWA deficiency enhances DNA damage in epidermal cells induced by DMBA, however, suppresses TPA-induced MEK-ERK activation, cell proliferation, and formation of skin papillomas. These data has potential clinical implications for targeting JWA in chemoprevention and therapy of skin tumors. or total amounts of JNK and p38 were detected by Western blotting. Each experiment was performed in triplicate. Supporting Information treated with DMBA/TPA. PCNA expression in the skin of JWA+/+ and JWAD2/D2 mice treated with DMBA/TPA was analyzed at mRNA level by real-time PCR and protein level by Western blotting. P,0.05. Typical PCNA immunostaining in skin from JWA+/+ and JWAD2/D2 mice. Arrows indicate PCNA-positive cells. The numbers of PCNA positive epidermal cells were counted from at least 100 cells in five separate fields for each section. P,0.05. Data were presented as means 6 s.d. from three independent experiments. in JWA+/+ and JWAD2/D2 mouse skin and keratinocytes. Skin lysates were prepared in tissue protein extraction buffer from JWA+/+ and JWAD2/D2 mouse skin treated with DMBA/ TPA at the end point of experiment. Total protein from paired samples was run on SDS-PAGE and probed with antibodies for phosphorylated or total amounts of JNK and p38. JWA+/+ and JWAD2/D2 keratinocytes were treated with 100 ng/ml TPA for the time period indicated, and phosphorylated Acknowledgments The authors thank Dr. Yihong Zhong in Department of Pathology, the Safety Assessment and Research Center for Drugs, Jiangsu Province, Nanjing Medical University for the assistance of immunohitochemistry analysis. Author Contributions Conceived and designed the experiments: ” ZG GL J. Zhou. Performed the experiments: ZG ZZ YS XL 8663121 YY J. Zhang AL. Analyzed the data: ZG ZZ XL J. Zhang. Contributed reagents/materials/analysis tools: ZG ZZ AL. Wrote the paper: ZG GL J. Zhou. References 1. Carrano AV, Minkler JL, Dillehay LE, Thompson LH Incorporated bromodeoxyuridine enhances the sister-chromatid exchange and chromosomal aberration frequencies in an EMS-sensitive Chinese hamster cell line. Mutat Res 162: 233239. 2. Dominguez I, Daza P, Natarajan AT, Cortes F A high yield of translocations parallels the high yield of sister chromatid exchanges in the CHO mutant EM9. Mutat Res 398: 6773. 3. Caldecott KW Single-strand break repair and genetic disease. Nat Rev Genet 9: 619631. 4. Hanahan D, Weinberg RA The hallmarks of cancer. Cell 100: 5770. 5. Denhardt DT Signal-transducing protein phosphorylation cascades mediated by Ras/Rho proteins in the mammalian cell: the potential for multiplex signalling. Biochem J 318: 729747. 6. Marshall CJ Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80: 179185. 7. Schaeffer HJ, Weber MJ Mitogen-activated protein kinases: specific messages from ubiquitous messengers. Mol Cell Biol 19: 24352444. 8. Hao D, Gao P, Liu P, Zhao J, Wang Y, et al. AC3-33, a novel secretory protein, inhibits Elk1 transcriptional activity via ERK pathw